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Revisiting Bacterial Interference in the Age of Methicillin-resistant Staphylococcus aureus

Insights Into Staphylococcus aureus Carriage, Pathogenicity and Potential Control

Planet, Paul J. MD, PhD*; Parker, Dane PhD; Ruff, Naomi L. PhD; Shinefield, Henry R. MD§,¶

The Pediatric Infectious Disease Journal: September 2019 - Volume 38 - Issue 9 - p 958–966
doi: 10.1097/INF.0000000000002411
Review Article

Bacteria compete with each other for local supremacy in biologic and environmental niches. In humans, who host an array of commensal bacteria, the presence of one species or strain can sometimes prevent colonization by another, a phenomenon known as “bacterial interference.” We describe how, in the 1960s, infants (and later adults) were actively inoculated with a relatively benign strain of Staphylococcus aureus, 502A, to prevent colonization with an epidemic S. aureus strain, 80/81. This introduced bacterial interference as a clinical approach to disease prevention, but little was known about the mechanisms of interference at that time. Since then, much has been learned about how bacteria interact with each other and the host to establish carriage, compete for niches and shift from harmless commensal to invasive pathogen. We provide an overview of these findings and summarize recent studies in which the genome and function of 502A were compared with those of the current epidemic strain, USA300, providing insight into differences in their invasiveness and immunogenicity. Although staphylococcal vaccines have been developed, none has yet been approved for clinical use. Further studies of staphylococcal strains and the molecular characteristics that lead to exclusion of specific bacteria from some niches may provide an alternative path to disease prevention.

From the *Department of Pediatrics University of Pennsylvania & Pediatric Infectious Diseases, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania

Department of Pathology, Immunology and Laboratory Medicine, Center for Immunity and Inflammation, Rutgers New Jersey Medical School, Newark, New Jersey

RuffDraft Communications LLC Duluth, Minnesota

§Department of Pediatrics, Kaiser Permanente, San Francisco, California (emeritus)

Departments of Pediatrics and Dermatology University of California, San Francisco, California (emeritus).

Accepted for publication June 4, 2019.

P.J.P. is supported by a grant from National Institutes of Health (NIH) (R01AI137526-01), and D.P. is supported by grants from NIH (R01HL134870) and the New Jersey Health Foundation (PC 62-19).

The authors have no conflicts of interest to disclose.

P.J.P. and D.P. contributed equally to this work.

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal’s website (

Address for correspondence: Henry R. Shinefield, MD, 15 East 69th Street Apt. 12A New York, NY 10021. E-mail:

Bacterial species and strains compete with each other within environmental and biologic niches.1 The recent focus on the human microbiome as a major determinant of disease has highlighted the role of bacterial competition in ecologic niches such as the gut, oral cavity and nose, although evidence for the role of competition in maintaining a stable balance of microorganisms goes back many decades.2 It has also been known for well over a century that the presence of one bacterial species can prevent the growth of, or colonization by, a second disease-causing organism,3,4 a concept that came to be known as “bacterial interference.”5 One modern application of this concept is the use of fecal transplants to treat Clostridium difficile infections that occur after antibiotics have disrupted the normal microbiota.6,7

Here we review bacteria–bacteria and bacteria–host interactions in the context of historical and current Staphylococcus aureus epidemics, including the pioneering work of one of the authors (H.R.S.) in bacterial interference to stop epidemic and recurrent staphylococcal infections.8–14 We will also describe recent developments that have shed light on potential mechanisms underlying S. aureus virulence and interference,15,16 as well as future directions that have the potential to lead to safe, novel strategies for the prevention and treatment of staphylococcal disease.

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S. aureus is both a frequent human commensal and a major pathogen that can cause disease ranging from minor skin and soft-tissue infections to life-threatening systemic infections. About 20% of adults have been reported to carry 1 or more strains of S. aureus chronically but asymptomatically, and another 30% to carry strains intermittently.17 A recent study using next-generation sequencing methods suggested that the carriage rates could actually be as high as 85%.18 Along with this seemingly benign carriage, each year, S. aureus causes hundreds of thousands of infections that result in hospitalization in the United States alone, leading to many deaths and billions of dollars in costs.19–21

Most newborns readily acquire staphylococci within days of birth,22,23 although up to third appear never to be colonized.23–25 Rates of colonization increase over the first few weeks of life22,23,25 and then decline.22,24,25 In a study of Israeli children 0–40 months of age, rates decreased from 25% at 0–3 months to 4% at 7–12 months, only to rise again to 9% at 25–40 months.26 Rates of carriage reported in older children are generally considerably higher, ranging from about 20%27,28 to >50%,29,30 similar to the rates in adults.17 In the United States in 2001–2002, the highest rate of colonization across the lifespan, ≈45%, was in children 6–11 years of age.31 In northern India, however, rates were higher in children 10–15 years of age (62%) than in those 5–9 years of age (48%).30 Changes in S. aureus carriage rates with age may, in part, be affected by differences in exposure to, and acquisition of, other bacteria, such as Streptococcus pneumoniae.24 Carriage of S. pneumoniae and S. aureus is inversely related,32 and in children, carriage of S. pneumoniae halves the risk of carrying S. aureus.26

Although the nares are often thought to be the major reservoir of S. aureus carriage, these bacteria can be isolated from the skin of many body sites. Studies that have examined both nasal and oropharyngeal carriage22,29 have shown that some children carry S. aureus in the throat but not in the nose, and a minority are colonized in both locations. Temporal patterns also differ between the 2 sites: in neonates in the United States, the throat had lower rates of carriage initially, but carriage often persisted longer in the throat than in the nose.22 A study in Italy found that nasal carriage in older children decreased with age (From 39% in children under 10 years to 18% in those at least 15 years), similar to the findings in the United States,31 but oropharyngeal carriage increased in these groups from 21% in children younger than 10 years to 26% in those 15 years of age or older. Other body sites frequently associated with S. aureus carriage include the axilla, groin and hands.17,33,34 Hands are particularly notable because they readily spread S. aureus to other people or to environmental fabrics or plastics, where they can survive for several weeks.35

About 40% of households have at least 1 member who is colonized.36 Most of the time, carriage of S. aureus does not lead to disease.36 However, when disease does occur, it is frequently caused by a strain carried in the nose,37,38 which may have undergone adaptive changes enabling systemic invasion.38 Nasal carriers are 3 times as likely to develop S. aureus bacteremia as noncarriers, but noncarriers with bacteremia are more likely to die,39 suggesting a complex relationship between the bacteria and the host immune system.

Supporting the role of carriage as a precursor for disease, decolonization strategies using topical antimicrobials such as mupirocin reduce the incidence of nosocomial staphylococcal infections in patients undergoing surgery40–42 and other health care procedures.43 However, staphylococci readily acquire resistance to antibiotics,44 limiting the usefulness of these drugs in the long term and making eradication difficult. Unfortunately, attempts to develop a vaccine have not yet been successful, although several are currently in development.45,46 Additional methods are therefore needed to prevent and control staphylococcal disease.

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Bacterial, host and environmental factors all play roles in determining carriage status,17,47,48 and affect the likelihood that S. aureus will shift from a commensal to an invasive phenotype.6S. aureus strains are quite diverse, in part because of the many mobile elements encoded in the S. aureus genome that enable the exchange of genetic information between strains and the ready acquisition of antibiotic resistance.49,50 Bacteriophages can also introduce new genetic elements through transduction.51 Indeed, strain diversity was historically defined by phage typing—that is, the susceptibility of each strain to lysis by specific bacteriophages52—as well as by serology and the antibiotic-resistance profile. Currently, strains are usually identified through genetic sequencing methods, such as multilocus sequence typing and variation in the S. aureus–specific protein A gene (spa typing).53 More recently, whole-genome sequencing has become the standard.49,54

S. aureus strains express a wide variety of virulence factors that function in the attachment of the bacteria to host cells [eg, wall teichoic acid (WTA), clumping factors], intoxification of host cells [eg, α-hemolysin (α-toxin), Panton–Valentine leukocidin (PVL)] and evasion of host defenses [eg, protein A, enterotoxins, capsular polysaccharides (CPs)].55 These factors promote colonization (Table 1) and can also contribute directly to disease, including the destruction of tissue.56,57



Proteins displayed on the surface of S. aureus, some of which are linked to peptidoglycan in the cell wall (Fig. 1), can contribute to adhesion, invasion and evasion.56 These proteins vary substantially among strains; indeed, as noted above, variation in protein A (spa typing) is used to distinguish strains from each other. Protein A is expressed at higher levels in carried strains than in noncarried strains, suggesting that it may have a role in establishing carriage.58 Surface proteins that mediate adhesion of S. aureus to host cells are particularly important for establishing carriage. These include WTA,47,59 as well as clumping factor B (ClfB)56,59 and iron-regulated surface determinant A, which promote colonization in humans through interactions with loricrin (Fig. 1).56,59,60 WTA is more active during the initial interactions between S. aureus and desquamated nasal epithelial cells within the inner nasal cavity,47,59 whereas ClfB and iron-regulated surface determinant A are more important for binding to anterior nasal surfaces1 and in persistence of carriage.61 A study of an S. aureus mutant lacking WTA underscored the link between carriage and virulence by showing both deficient binding of the mutants to endothelial cells and a reduction in their proliferation and dissemination to end organs in an animal model of endocarditis.62 Methicillin-resistant S. aureus epidemic strains with high levels of WTA also induced more abscesses than strains with low levels of WTA in an animal model.63



Although no vaccine has yet been approved for clinical use, many S. aureus virulence factors have been tested as vaccine antigens, with mixed success. A phase 3 trial of a vaccine containing CP5 and CP8 (StaphVax; Nabi Biopharmaceuticals, Rockville, Maryland Biopharmaceuticals, Rockville, Maryland) examined the rate of bacteremia in patients with end-stage renal disease who were receiving hemodialysis.64 Most patients responded to the vaccine, and in a post hoc analysis, it provided significant protection against bacteremia from weeks 3 to 40 (estimated efficacy, 57%; P = 0.02). In addition, a permutation test determined that the incidence of bacteremia was significantly lower in the vaccine group than in controls between weeks 3 and 32 (log-rank statistic, 7.03; exact P = 0.05).64,65 However, it failed to reach significance on the primary outcome of difference in bacteremia at week 54 (estimated efficacy, 26%; P = 0.23), and therefore, did not receive Food and Drug Administration approval. A phase 3 trial of an iron-regulated surface determinant B vaccine (V710; Merck, Kenilworth, New Jersey) was stopped early because of increased mortality in subjects vaccinated after heart surgery.66 The candidate vaccine currently furthest along in clinical studies, SA4Ag (Pfizer, New York), includes 4 antigens: CP5; CP8; clumping factor A, which binds the extracellular matrix protein fibrinogen; and the Manganese transport protein C (MntC). It showed positive results in a phase 1/2 study45 and is currently in a phase 2 study of patients undergoing spinal surgery (STRIVE, NCT02388165). Another tetravalent vaccine containing CP5, CP8, clumping factor A and α-toxin produced functional antibodies in a recent phase 1 study,67 but this vaccine has not been developed further.68 A vaccine containing α-toxin and PVL was safe and immunogenic in a recent phase 1 trial,69 but it is unclear whether future studies are planned. A number of other formulations including these and other virulence factors (eg, WTA, protein A, ClfB) have been tested in preclinical studies.70–72

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Staphylococcal proteins also interact with the host immune system. For example, the ligand for WTA, scavenger receptor expressed by endothelial cells 1 (SREC-1), triggers innate immune system signaling through Toll-like receptors (Fig. 1).47,73 Strains that are persistently carried may trigger less of an immune response than noncarried strains, preventing or delaying their clearance.58,74 Protein A also interacts with the host immune system to produce both pro- and anti-inflammatory responses.56 It binds to the Crystallizable fragment (Fc) region of immunoglobulin G, resulting in incorrectly oriented antibodies and preventing phagocytosis and the activation of complement. It also binds to receptors on B cells, interfering with B-cell function and thereby potentially reducing vaccine efficacy.75 Furthermore, its interactions with tumor necrosis factor receptors on the lung epithelial cells of mice activate intracellular signaling, recruit neutrophils and result in increased inflammation and tissue damage.76 At the same time, protein A regulates tumor necrosis factor signaling through interactions with the epidermal growth factor receptor, which reduces the inflammatory response.77

Conversely, numerous host immune factors influence the ability of S. aureus to establish carriage.47 Nasal fluid from carriers contains fewer antimicrobial proteins than nasal fluid from noncarriers and is more permissive for S. aureus growth in vitro and carriage in vivo78; the specific host immune response appears to be a primary determinant of the length of carriage.79 The host also generates an antigen-specific adaptive immune response to S. aureus, which, unfortunately, does not appear to protect against recurrent or chronic infections.80 Instead, staphylococci are able to counteract or even co-opt the host immune system through various mechanisms, such as the induction of regulatory T cells, dendritic cell tolerance and the expansion of myeloid-derived suppressor cells.80S. aureus can thus simultaneously activate and inactivate various parts of the immune system.81

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The nasal cavity is a competitive environment for bacteria, and the microbiota can influence both the presence and abundance of S. aureus.82 Different species compete for space and nutrients and may actively limit competitive species through the production of antibiotics, such as bacteriocins.1 Although most staphylococcal bacteriocins are not effective against S. aureus, lugdunin, an antimicrobial compound produced by nasal Staphylococcus lugdunensis, can kill or suppress S. aureus (Fig. 2).1,83 As a result, colonization with S. lugdunensis reduces the risk of S. aureus carriage 6-fold.1 Coagulase-negative strains such as Staphylococcus epidermidis can also limit colonization by S. aureus through the production of antimicrobial enzymes84 such as extracellular serine protease (Esp),85 which possibly interferes with S. aureus colonization by degrading its surface adhesins or ligands for epithelial proteins.1 Esp-secreting S. epidermidis can eliminate S. aureus nasal colonization in human carriers.85 Interestingly, S. aureus does not readily become resistant to Esp or lugdunin as it does to so many clinically used antibiotics.81 In fact, treatment with topical antibiotics can, at least in mice, lead to increases in S. aureus numbers by removing commensal staphylococcal strains that normally inhibit S. aureus colonization and growth.86



The “accessory gene regulation” (agr) system also appears to provide a mechanism for competition between bacterial species and between strains of S. aureus. This system senses cell density and is associated with a switch from the expression of adhesins and other colonizing factors to the expression of toxins and degradative enzymes.20 Thus, the agr system may be related to the switch between carriage and invasion.87 Supporting this, S. aureus cocultured with Corynebacterium spp. undergoes a shift in gene expression away from the virulence-associated genes of the agr system and toward genes associated with colonization, including protein A, leading to a less pathogenic phenotype.88S. aureus strains can be divided into 4 groups (I–IV) on the basis of activation of the agr response.89,90 The autoinducing peptide (AIP) generated by the AgrB and AgrD loci activates the strain that produces it and others within the same group, but in general inhibits the agr response in strains from the other groups.90,91 Inhibition by AIP thus provides one potential mechanism for competition between S. aureus strains, as well as between staphylococcal species.92 Although not all studies have supported this as a function of AIP,93 drugs targeting various parts of the agr system are being investigated as a means of treating or preventing S. aureus disease.94

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In the mid-20th century, an S. aureus strain of phage type 80/81 began to cause outbreaks of severe disease. Although this strain was apparently present as early as the 1920s,95 it was first identified in Australian newborns and their mothers in 195396, 97 and was soon also found in adult patients and staff in the same hospital, as well as in other hospitals in Australia.97 Skin lesions such as abscesses and pustules were particularly prominent in infants and adults, although pneumonia, sepsis and other cases of invasive disease were also seen and were sometimes fatal.97,98

By the end of the 1950s and into the 1960s, 80/81 had become an epidemic strain responsible for hospital-acquired infections worldwide,98–101 particularly affecting nurseries and surgical wards.8 However, carriage was not always immediately apparent in newborns,102 and initially asymptomatic infants sometimes developed staphylococcal disease weeks or months after being brought home.102,103 In the meantime, some infected their nursing mothers,10,98 who developed mastitis and breast abscesses. Other family members also became colonized,10,102 leading to staphylococcal disease that “ping-ponged” through households for months or years.98 Hospital staff identified as carriers were put on leave to prevent spread.8,101,103

The vast majority of 80/81 isolates were resistant to penicillin,97,98 and some were resistant to additional antibiotics.98,99 A recent investigation into the 80/81 genome determined that, unlike many current hospital strains, 80/81 had a fully functional agr system and produced a full-length version of α-toxin,104 which disrupts epithelial integrity and suppresses immune responses105; these features likely contributed to its virulence.

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In the early 1960s, an 80/81 nursery outbreak occurred despite the implementation of extensive infection control measures. Two complementary observations suggested that a biologic approach to preventing colonization with 80/81—ensuring prior colonization with a nonvirulent strain—might be effective for interrupting the outbreak.3,8 First, a nurse who was an 80/81 carrier cared for 37 infants during their first 24 hours of life, during which 8 (22%) were infected. By contrast, no infants that she cared for only after their first postnatal day were colonized with 80/81, but 26 (84%) were positive for other strains of coagulase-positive staphylococci. The discrepancy between the colonization rates on day 1 and later days suggested that the presence of one staphylococcal strain interferes with colonization by a second strain. To test this hypothesis, an experiment was set up in 2 nurseries with known 80/81 colonization rates.8 Neonates transferred at 16 hours of age from Nursery B, where the rate of 80/81 colonization was 11%, to Nursery A, where the rate was 56%, retained the lower rate of 80/81 colonization at discharge 4 or 5 days later (see Table, Supplemental Digital Content 1, Given that 80% of the transferred infants had been colonized with coagulase-positive staphylococci before their transfer, the results suggested that interference, rather than age, was the critical factor.

Second, a group of infants was discovered to have been colonized by a staphylococcal strain, dubbed 502A, and none of these infants acquired 80/81. This raised the possibility of using 502A in an intentional campaign of bacterial interference to prevent the acquisition of the epidemic strain.3,8,11 Importantly, 502A had the characteristics necessary for such clinical use of bacterial interference: low potential for disease, the ability to colonize and persist in the patient, readily identifiable in the laboratory and susceptible to antibiotics. Although the phage typing of 502A was somewhat variable,8,106 its serology and antibiotic susceptibilities were consistent across phage profiles.107 A year of follow-up showed that 502A was not associated with skin, eye, breast, gastrointestinal or respiratory disease in the colonized infants or their family members.8 Over this time, 502A also retained its characteristics, including susceptibility to penicillin.8 It is now available through ATCC as strain 27217.108

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Dr. Shinefield then initiated programs of active bacterial interference in nurseries across the country that were experiencing 80/81 outbreaks. A series of reports8–12 showed that inoculating the noses and umbilical stumps of neonates led to stable carriage of 502A over several months (see Table, Supplemental Digital Content 2, and lowered both the acquisition of 80/81 (Table 2) and the incidence of staphylococcal lesions. This approach was deemed to be “well supported by clinical, epidemiologic and serologic evidence” in the words of an accompanying editorial by Dubos.109 Other groups then began similar efforts, although specific practices sometimes differed. In particular, although small numbers had been shown to be sufficient to achieve colonization (>80% success with >500 bacteria applied to the nose or 55 bacteria applied to the umbilical site),8 some groups used inocula up to an estimated 50,000 bacteria.110,111



Adults and families were also treated with 502A, successfully interrupting ping-pong transmission through households.14,106,112–116 However, resident strains usually had to be cleared with antibiotics before 502A would take, further reinforcing the idea that the presence of one strain of S. aureus can interfere with the acquisition of a second strain.3,13 This was corroborated in a gnotobiotic mouse model, where 502A administered into the gastrointestinal tracts of mice prevented the proliferation of subsequently administered 80/81, although 80/81 did not similarly prevent the proliferation of 502A in this model.117

Despite its apparently low disease potential, on rare occasions, 502A was associated with disease, most often when high numbers of bacteria were applied.111,118,119 Localized pustules or conjunctivitis were seen in some infants,12,110,111 and self-limiting abscesses were reported in a few cases. Unfortunately, one death from septicemia occurred after 502A was applied to the umbilicus and nares of a premature, hypoglycemic child born to a mother with diabetes111; notably, a catheter was inserted into the umbilical vein to deliver glucose several hours after 502A was applied, potentially introducing 502A into the bloodstream.

It was appreciated at the time that understanding the mechanism of bacterial interference might permit the use of isolated molecules, rather than live bacteria, to prevent colonization of virulent strains, further increasing the safety of this approach. Many investigations were made into the possible mechanisms of interference in the 1960s and 1970s.3 One finding was that teichoic acid, a molecule involved in attachment of S. aureus to the nasal epithelium,62 inhibited S. aureus attachment in vitro by 71%.120 However, many details of the mechanism remained elusive. With time, the success of continued colonization of newborns with 502A, and the introduction of methicillin, the 80/81 epidemic waned and these studies were not pursued.

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More than 30 years after the 80/81 epidemic abated, new methicillin-resistant S. aureus strains, most notably USA300, emerged as epidemic strains.21,121,122 USA300 is also readily transmissible,123 has affected newborns and their mothers,124,125 and has spread through households.126,127 Recently, 2 of the authors (P.J.P., D.P.) and their colleagues undertook a comparison of 502A and USA300 to determine why 502A typically is not associated with severe disease,16 whereas USA300 is invasive and virulent.21

In vitro studies confirmed that 502A is less likely than USA300 to cross epithelial barriers (Table 3). It was <40% as successful as USA300 in invading human keratinocytes and nasal epithelial cells (Fig. 3A) and was an order of magnitude less efficient in crossing an epithelial monolayer of cells (Fig. 3B).16 Despite this difference in invasiveness, the genomic sequence of 502A15 indicated that 502A and USA300 contain similar virulence factors, including α-toxin, leukocidins, adhesion factors, protein A, iron acquisition genes, phenol soluble modulins and regulatory factors (Table 3).16 Although the strains differed in their enterotoxin genes and 502A does not encode PVL, 502A nonetheless possesses many virulence factors associated with disease, suggesting that it would be a capable pathogen. Indeed, when a large number of bacteria were delivered deep into the lungs of mice, likely resulting in some that crossed the epithelial barrier, 502A proved to be dramatically more lethal than USA300.16 All mice inoculated intranasally with 7 × 107 colony-forming units of USA300 survived, whereas all mice inoculated with the same number of 502A died (see Fig., Supplemental Digital Content 3, In a nonlethal mouse acute pneumonia model, 502A was significantly more virulent than USA300, with increased bacterial burden in lung tissue and a more robust immune response. This new understanding of 502A’s potential for virulence when introduced beyond superficial tissues may explain the single infant death attributed to bacterial interference with 502A. It also highlights the risks of using live bacteria as a means of interference.





The similarity in virulence factors between 502A and USA300 suggested that these factors were not the cause of the higher mortality with 502A in the mouse studies. Instead, the host immune response may be to blame. In the mouse acute pneumonia model, the enhanced immune response of 502A was characterized by significantly greater concentrations of the inflammatory cytokines CXCL1/KC and interleukin-6, in addition to increased recruitment of dendritic cells and natural killer cells.16 Induction of type I interferon (IFN) is a normal part of the innate immune response to viral and bacterial infection, but IFN has complex effects through multiple pathways and can be detrimental to the host rather than the pathogen.128 Stimulation of mouse lung epithelial cells with 502A induced 100-fold more IFN than stimulation with USA300 (Fig. 4), suggesting that host signaling through IFN may contribute to the increased morbidity and mortality seen with 502A infection of the lung. Strain 502A also appears to activate IFN through a different mechanism than USA300: whereas USA300 activates type I IFN signaling through Toll-like receptor 9,129 502A uses NOD2 (a receptor for peptidoglycan). Furthermore, 502A exhibited increased autolysis, which leads to the release of peptidoglycan from the cell wall, stimulating NOD2 and activating the type I IFN pathway.16 However, live bacteria were required for this IFN response to 502A, so the peptidoglycan of 502A is not inherently more stimulatory than that of USA300; this phenomenon will therefore need to be investigated further. The role of the IFN pathway in morbidity and mortality was confirmed in mice lacking the type I IFN receptor (Ifnar−/− mice): Ifnar−/− mice infected with 502A sustained less lung damage, had lower bacterial burdens in bronchoalveolar lavage fluid, and had lower concentrations of inflammatory cytokines than wild-type mice. Furthermore, in a mortality model, 50% of the Ifnar knockouts survived, whereas only 8% of the wild-type mice survived. These comparative data suggest that 502A may exclude invasive S. aureus strains by stimulating the host immune system while remaining relatively noninvasive itself.



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In the face of the severe and persistent disease caused by strain 80/81, the low incidence of 502A disease was a reasonable tradeoff. However, our new understanding of the potential lethality of 502A removes it, in its present form, as an option for future clinical use in newborns. Nonetheless, it makes an excellent model for investigating the host and bacterial mechanisms underlying the interference phenomenon, which could then be used to develop a safer and more targeted intervention for prophylaxis and treatment.

Carriage of S. aureus is so widespread that it is essentially a normal condition. However, there is great diversity in which strains are carried and for how long. One question is therefore what determines the individual pattern of carriage. A more detailed examination of the natural variation in S. aureus strains carried by individuals, the immune responses that each of these strains elicit in vivo and in vitro and their duration of carriage would give insight into how tightly the phenotypes of immunostimulation and persistence are linked.

How each strain stimulates the immune response is another crucial question. USA300 and 502A contain very similar virulence factors yet have opposite phenotypes for immunostimulation and invasiveness. We do not know whether any of the virulence factors are necessary for immunostimulation and the exclusion of other strains, or whether it would be possible to separate the specific factors responsible for the protective interference phenotype from those responsible for invasion and pathogenesis. We plan to use genetic approaches—the creation of targeted mutants and screens of mutant libraries—to isolate factors responsible for these phenotypes, or at least to greatly attenuate virulence while retaining the immunostimulation and interference. Because 502A releases more peptidoglycan than USA300, this molecule is an early candidate for examination. WTA, which is covalently attached to peptidoglycan, is another target. A goal is to identify specific molecules that could effectively evoke the interference phenotype while remaining safe for clinical use.

The competition between single strains also needs to be placed in the context of the entire microbial assemblage of the skin and mucous membranes where S. aureus is carried. Interest in the human microbiota and our technical ability to examine its diversity have grown in recent years, and we expect that our understanding of the complex interactions among microbes and their hosts, as well as how bacteria compete with each other, will continue to progress rapidly, providing additional candidate molecules and mechanisms for use in bacterial interference.

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1. Krismer B, Weidenmaier C, Zipperer A, et al. The commensal lifestyle of Staphylococcus aureus and its interactions with the nasal microbiota. Nat Rev Microbiol. 2017;15:675–687.
2. Sprunt K, Redman W. Evidence suggesting importance of role of interbacterial inhibition in maintaining balance of normal flora. Ann Intern Med. 1968;68:579–590.
3. Shinefield HR, Ribble JC, Boris M, et al. Cohen JO. Chapter twenty-two: bacterial interference. In: The Staphylococci. 1972.New York, NY: John Wiley & Sons, Inc..
4. Florey HW. The use of micro-organisms for therapeutic purposes. Yale J Biol Med. 1946;19:101–117.
5. Henderson DW. Bacterial interference. Bacteriol Rev. 1960;24:167–176.
6. Chen YE, Fischbach MA, Belkaid Y. Skin microbiota-host interactions. Nature. 2018;553:427–436.
7. Rohlke F, Stollman N. Fecal microbiota transplantation in relapsing Clostridium difficile infection. Therap Adv Gastroenterol. 2012;5:403–420.
8. Shinefield HR, Ribble JC, Boris M, et al. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. I. Preliminary observations on artificial colonzation of newborns. Am J Dis Child. 1963;105:646–654.
9. Shinefield HR, Sutherland JM, Ribble JC, et al. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. II. The Ohio epidemic. Am J Dis Child. 1963;105:655–662.
10. Shinefield HR, Boris M, Ribble JC, et al. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. III. The Georgia epidemic. Am J Dis Child. 1963;105:663–673.
11. Boris M, Shine Field HR, Ribble JC, et al. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. IV. The Louisiana epidemic. Am J Dis Child. 1963;105:674–682.
12. Shinefield HR, Ribble JC, Eichenwald HF, et al. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. V. An analysis and interpretation. Am J Dis Child. 1963;105:683–688.
13. Shinefield HR, Wilsey JD, Ribble JC, et al. Interactions of staphylococcal colonization. Influence of normal nasal flora and antimicrobials on inoculated Staphylococcus aureus strain 502A. Am J Dis Child. 1966;111:11–21.
14. Boris M, Shinefield HR, Romano P, et al. Bacterial interference. Protein against recurrent intrafamilial staphylococcal disease. Am J Dis Child. 1968;115:521–529.
15. Parker D, Narechania A, Sebra R, et al. Genome sequence of bacterial interference strain Staphylococcus aureus 502A. Genome Announc. 2014;2:e0028414.
16. Parker D, Planet PJ, Soong G, et al. Induction of type I interferon signaling determines the relative pathogenicity of Staphylococcus aureus strains. PLoS Pathog. 2014;10:e1003951.
17. Wertheim HF, Melles DC, Vos MC, et al. The role of nasal carriage in Staphylococcus aureus infections. Lancet Infect Dis. 2005;5:751–762.
18. Lu YJ, Sasaki T, Kuwahara-Arai K, et al. Development of a new application for comprehensive viability analysis based on microbiome analysis by next-generation sequencing: insights into staphylococcal carriage in human nasal cavities. Appl Environ Microbiol. 2018;84:e0051718.
19. Suaya JA, Mera RM, Cassidy A, et al. Incidence and cost of hospitalizations associated with Staphylococcus aureus skin and soft tissue infections in the United States from 2001 through 2009. BMC Infect Dis. 2014;14:296.
20. Balasubramanian D, Harper L, Shopsin B, et al. Staphylococcus aureus pathogenesis in diverse host environments. Pathog Dis. 2017;75.
21. Klevens RM, Morrison MA, Nadle J, et al; Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillin-resistant Staphylococcus aureus infections in the United States. JAMA. 2007;298:1763–1771.
22. Hurst V. Staphylococcus aureus in the infant upper respiratory tract. I. Observations on hospital-born babies. J Hyg (Lond). 1957;55:299–312.
23. Maayan-Metzger A, Strauss T, Rubin C, et al. Clinical evaluation of early acquisition of Staphylococcus aureus carriage by newborns. Int J Infect Dis. 2017;64:9–14.
24. Lebon A, Labout JA, Verbrugh HA, et al. Dynamics and determinants of Staphylococcus aureus carriage in infancy: the Generation R Study. J Clin Microbiol. 2008;46:3517–3521.
25. Peacock SJ, Justice A, Griffiths D, et al. Determinants of acquisition and carriage of Staphylococcus aureus in infancy. J Clin Microbiol. 2003;41:5718–5725.
26. Regev-Yochay G, Raz M, Carmeli Y, et al; Maccabi Implementing Judicious Antibiotic Prescription Study Group. Parental Staphylococcus aureus carriage is associated with staphylococcal carriage in young children. Pediatr Infect Dis J. 2009;28:960–965.
27. Oguzkaya-Artan M, Baykan Z, Artan C. Nasal carriage of Staphylococcus aureus in healthy preschool children. Jpn J Infect Dis. 2008;61:70–72.
28. Eibach D, Nagel M, Hogan B, et al. Nasal carriage of Staphylococcus aureus among children in the Ashanti Region of Ghana. PLoS One. 2017;12:e0170320.
29. Esposito S, Terranova L, Zampiero A, et al. Oropharyngeal and nasal Staphylococcus aureus carriage by healthy children. BMC Infect Dis. 2014;14:723.
30. Chatterjee SS, Ray P, Aggarwal A, et al. A community-based study on nasal carriage of Staphylococcus aureus. Indian J Med Res. 2009;130:742–748.
31. Kuehnert MJ, Kruszon-Moran D, Hill HA, et al. Prevalence of Staphylococcus aureus nasal colonization in the United States, 2001-2002. J Infect Dis. 2006;193:172–179.
32. Bogaert D, van Belkum A, Sluijter M, et al. Colonisation by Streptococcus pneumoniae and Staphylococcus aureus in healthy children. Lancet. 2004;363:1871–1872.
33. Kluytmans J, van Belkum A, Verbrugh H. Nasal carriage of Staphylococcus aureus: epidemiology, underlying mechanisms, and associated risks. Clin Microbiol Rev. 1997;10:505–520.
34. Knox J, Uhlemann AC, Lowy FD. Staphylococcus aureus infections: transmission within households and the community. Trends Microbiol. 2015;23:437–444.
35. Neely AN, Maley MP. Survival of Enterococci and Staphylococci on hospital fabrics and plastic. J Clin Microbiol. 2000;38:724–726.
36. Miller M, Cook HA, Furuya EY, et al. Staphylococcus aureus in the community: colonization versus infection. PLoS One. 2009;4:e6708.
37. von Eiff C, Becker K, Machka K, et al. Nasal carriage as a source of Staphylococcus aureus bacteremia. Study Group. N Engl J Med. 2001;344:11–16.
38. Young BC, Wu CH, Gordon NC, et al. Severe infections emerge from commensal bacteria by adaptive evolution. Elife. 2017;6:e30637.
39. Wertheim HF, Vos MC, Ott A, et al. Risk and outcome of nosocomial Staphylococcus aureus bacteraemia in nasal carriers versus non-carriers. Lancet. 2004;364:703–705.
40. Chen AF, Wessel CB, Rao N. Staphylococcus aureus screening and decolonization in orthopaedic surgery and reduction of surgical site infections. Clin Orthop Relat Res. 2013;471:2383–2399.
41. van Rijen MM, Bonten M, Wenzel RP, et al. Intranasal mupirocin for reduction of Staphylococcus aureus infections in surgical patients with nasal carriage: a systematic review. J Antimicrob Chemother. 2008;61:254–261.
42. Bode LG, Kluytmans JA, Wertheim HF, et al. Preventing surgical-site infections in nasal carriers of Staphylococcus aureus. N Engl J Med. 2010;362:9–17.
43. Nair R, Perencevich EN, Blevins AE, et al. Clinical effectiveness of mupirocin for preventing Staphylococcus aureus infections in nonsurgical settings: a meta-analysis. Clin Infect Dis. 2016;62:618–630.
44. Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol. 2009;7:629–641.
45. Frenck RW Jr, Creech CB, Sheldon EA, et al. Safety, tolerability, and immunogenicity of a 4-antigen Staphylococcus aureus vaccine (SA4Ag): results from a first-in-human randomised, placebo-controlled phase ½ study. Vaccine. 2017;35:375–384.
46. Giersing BK, Dastgheyb SS, Modjarrad K, et al. Status of vaccine research and development of vaccines for Staphylococcus aureus. Vaccine. 2016;34:2962–2966.
47. Mulcahy ME, McLoughlin RM. Host-bacterial crosstalk determines Staphylococcus aureus nasal colonization. Trends Microbiol. 2016;24:872–886.
48. Sakr A, Brégeon F, Mège JL, et al. Staphylococcus aureus nasal colonization: an update on mechanisms, epidemiology, risk factors, and subsequent infections. Front Microbiol. 2018;9:2419.
49. Planet PJ, Narechania A, Chen L, et al. Architecture of a species: phylogenomics of Staphylococcus aureus. Trends Microbiol. 2017;25:153–166.
50. Moreillon P, Que Y-A, Glauser M. Mandell G, Bennett J, Dolin R. Staphyloccocus aureus (including Staphylococcal toxic shock). In: Mandell, Douglas, and Bennett’s Principles and Practices of Infectious Diseases. 2005:6th ed. Philadelphia, PA: Elsevier Churchill Livingstone; 2321–2351.
51. Canchaya C, Fournous G, Chibani-Chennoufi S, et al. Phage as agents of lateral gene transfer. Curr Opin Microbiol. 2003;6:417–424.
52. Blair JE, Williams RE. Phage typing of staphylococci. Bull World Health Organ. 1961;24:771–784.
53. Missiakas D, Schneewind O. Staphylococcus aureus vaccines: deviating from the carol. J Exp Med. 2016;213:1645–1653.
54. Aanensen DM, Feil EJ, Holden MT, et al. Whole-genome sequencing for routine pathogen surveillance in public health: a population snapshot of invasive Staphylococcus aureus in Europe. MBio. 2016;7:e0044416.
55. Thammavongsa V, Kim HK, Missiakas D, et al. Staphylococcal manipulation of host immune responses. Nat Rev Microbiol. 2015;13:529–543.
56. Foster TJ, Geoghegan JA, Ganesh VK, et al. Adhesion, invasion and evasion: the many functions of the surface proteins of Staphylococcus aureus. Nat Rev Microbiol. 2014;12:49–62.
57. Tong SY, Davis JS, Eichenberger E, et al. Staphylococcus aureus infections: epidemiology, pathophysiology, clinical manifestations, and management. Clin Microbiol Rev. 2015;28:603–661.
58. Muthukrishnan G, Quinn GA, Lamers RP, et al. Exoproteome of Staphylococcus aureus reveals putative determinants of nasal carriage. J Proteome Res. 2011;10:2064–2078.
59. Winstel V, Kühner P, Salomon F, et al. Wall teichoic acid glycosylation governs Staphylococcus aureus nasal colonization. MBio. 2015;6:e00632.
60. Clarke SR, Andre G, Walsh EJ, et al. Iron-regulated surface determinant protein A mediates adhesion of Staphylococcus aureus to human corneocyte envelope proteins. Infect Immun. 2009;77:2408–2416.
61. Wertheim HF, Walsh E, Choudhurry R, et al. Key role for clumping factor B in Staphylococcus aureus nasal colonization of humans. PLoS Med. 2008;5:e17.
62. Weidenmaier C, Peschel A, Xiong YQ, et al. Lack of wall teichoic acids in Staphylococcus aureus leads to reduced interactions with endothelial cells and to attenuated virulence in a rabbit model of endocarditis. J Infect Dis. 2005;191:1771–1777.
63. Wanner S, Schade J, Keinhörster D, et al. Wall teichoic acids mediate increased virulence in Staphylococcus aureus. Nat Microbiol. 2017;2:16257.
64. Shinefield H, Black S, Fattom A, et al. Use of a Staphylococcus aureus conjugate vaccine in patients receiving hemodialysis. N Engl J Med. 2002;346:491–496.
65. Shinefield HR, Black S. Prevention of Staphylococcus aureus infections: advances in vaccine development. Expert Rev Vaccines. 2005;4:669–676.
66. Fowler VG, Allen KB, Moreira ED, et al. Effect of an investigational vaccine for preventing Staphylococcus aureus infections after cardiothoracic surgery: a randomized trial. JAMA. 2013;309:1368–1378.
67. Levy J, Licini L, Haelterman E, et al. Safety and immunogenicity of an investigational 4-component Staphylococcus aureus vaccine with or without AS03B adjuvant: results of a randomized phase I trial. Hum Vaccin Immunother. 2015;11:620–631.
68. Redi D, Raffaelli CS, Rossetti B, et al. Staphylococcus aureus vaccine preclinical and clinical development: current state of the art. New Microbiol. 2018;41:208–213.
69. Landrum ML, Lalani T, Niknian M, et al. Safety and immunogenicity of a recombinant Staphylococcus aureus α-toxoid and a recombinant Panton-Valentine leukocidin subunit, in healthy adults. Hum Vaccin Immunother. 2017;13:791–801.
70. Lacey KA, Mulcahy ME, Towell AM, et al. Clumping factor B is an important virulence factor during Staphylococcus aureus skin infection and a promising vaccine target. PLoS Pathog. 2019;15:e1007713.
71. Schaffer AC, Lee JC. Vaccination and passive immunisation against Staphylococcus aureus. Int J Antimicrob Agents. 2008;32(suppl 1):S71–S78.
72. Reddy PN, Srirama K, Dirisala VR. An update on clinical burden, diagnostic tools, and therapeutic options of Staphylococcus aureus. Infect Dis (Auckl). 2017;10:1179916117703999.
73. Murshid A, Borges TJ, Calderwood SK. Emerging roles for scavenger receptor SREC-I in immunity. Cytokine. 2015;75:256–260.
74. Quinn GA, Cole AM. Suppression of innate immunity by a nasal carriage strain of Staphylococcus aureus increases its colonization on nasal epithelium. Immunology. 2007;122:80–89.
75. Thomsen IP, Liu GY. Targeting fundamental pathways to disrupt Staphylococcus aureus survival: clinical implications of recent discoveries. JCI Insight. 2018;3:pii: 98216.
76. Gómez MI, Lee A, Reddy B, et al. Staphylococcus aureus protein A induces airway epithelial inflammatory responses by activating TNFR1. Nat Med. 2004;10:842–848.
77. Gómez MI, Seaghdha MO, Prince AS. Staphylococcus aureus protein A activates TACE through EGFR-dependent signaling. EMBO J. 2007;26:701–709.
78. Cole AM, Dewan P, Ganz T. Innate antimicrobial activity of nasal secretions. Infect Immun. 1999;67:3267–3275.
79. Cole AL, Muthukrishnan G, Chong C, et al. Host innate inflammatory factors and staphylococcal protein A influence the duration of human Staphylococcus aureus nasal carriage. Mucosal Immunol. 2016;9:1537–1548.
80. Goldmann O, Medina E. Staphylococcus aureus strategies to evade the host acquired immune response. Int J Med Microbiol. 2018;308:625–630.
81. Byrd AL, Belkaid Y, Segre JA. The human skin microbiome. Nat Rev Microbiol. 2018;16:143–155.
82. Liu CM, Price LB, Hungate BA, et al. Staphylococcus aureus and the ecology of the nasal microbiome. Sci Adv. 2015;1:e1400216.
83. Zipperer A, Konnerth MC, Laux C, et al. Human commensals producing a novel antibiotic impair pathogen colonization. Nature. 2016;535:511–516.
84. Nakatsuji T, Chen TH, Narala S, et al. Antimicrobials from human skin commensal bacteria protect against Staphylococcus aureus and are deficient in atopic dermatitis. Sci Transl Med. 2017;9:eaah4680.
85. Iwase T, Uehara Y, Shinji H, et al. Staphylococcus epidermidis Esp inhibits Staphylococcus aureus biofilm formation and nasal colonization. Nature. 2010;465:346–349.
86. SanMiguel AJ, Meisel JS, Horwinski J, et al. Topical antimicrobial treatments can elicit shifts to resident skin bacterial communities and reduce colonization by Staphylococcus aureus competitors. Antimicrob Agents Chemother. 2017;61:e0077417.
87. Le KY, Otto M. Quorum-sensing regulation in staphylococci-an overview. Front Microbiol. 2015;6:1174.
88. Ramsey MM, Freire MO, Gabrilska RA, et al. Staphylococcus aureus Shifts toward commensalism in response to corynebacterium species. Front Microbiol. 2016;7:1230.
89. Mayville P, Ji G, Beavis R, et al. Structure-activity analysis of synthetic autoinducing thiolactone peptides from Staphylococcus aureus responsible for virulence. Proc Natl Acad Sci U S A. 1999;96:1218–1223.
90. Wang B, Muir TW. Regulation of virulence in Staphylococcus aureus: molecular mechanisms and remaining puzzles. Cell Chem Biol. 2016;23:214–224.
91. Ji G, Beavis R, Novick RP. Bacterial interference caused by autoinducing peptide variants. Science. 1997;276:2027–2030.
92. Paharik AE, Parlet CP, Chung N, et al. Coagulase-negative Staphylococcal strain prevents Staphylococcus aureus colonization and skin infection by blocking quorum sensing. Cell Host Microbe. 2017;22:746–756.e5.
93. Lina G, Boutite F, Tristan A, et al. Bacterial competition for human nasal cavity colonization: role of Staphylococcal agr alleles. Appl Environ Microbiol. 2003;69:18–23.
94. Tan L, Li SR, Jiang B, et al. Therapeutic targeting of the Staphylococcus aureus Accessory Gene Regulator (agr) system. Front Microbiol. 2018;9:55.
95. Blair JE, Carr M. Distribution of phage groups of Staphylococcus aureus in the years 1927 through 1947. Science. 1960;132:1247–1248.
96. Isbister C, Durie EB, Rountree PM, et al. Further study of staphylococcal infection of the new-born. Med J Aust. 1954;2:897–900.
97. Rountree PM, Freeman BM. Infections caused by a particular phage type of Staphylococcus aureus. Med J Aust. 1955;42:157–161.
98. Rountree PM, Beard MA. Further observations on infection with phage type 80 staphylococci in Australia. Med J Aust. 1958;45:789–795.
99. Blair JE, Carr M. Staphylococci in hospital-acquired infections; types encountered in the United States. J Am Med Assoc. 1958;166:1192–1196.
100. Bynoe ET, Elder RH, Comtois RD. Phage-typing and antibiotic-resistance of staphylococci isolated in a general hospital. Can J Microbiol. 1956;2:346–358.
101. Nahmias AJ, Godwin JT, Updyke EL, et al. Postsurgical staphylococcic infections. Outbreak traced to an individual carrying phase strains 80/81 and 80/81/52/52A. JAMA. 1960;174:1269–1275.
102. Hurst V, Grossman M. The hospital nursery as a source of staphylococcal disease among families of newborn infants. N Engl J Med. 1960;262:951–956.
103. Shaffer TE, Sylvester RF Jr, Baldwin JN, et al. Staphylococcal infections in newborn infants. II. Report of 19 epidemics caused by an identical strain of staphylococcus pyogenes. Am J Public Health Nations Health. 1957;47:990–994.
104. DeLeo FR, Kennedy AD, Chen L, et al. Molecular differentiation of historic phage-type 80/81 and contemporary epidemic Staphylococcus aureus. Proc Natl Acad Sci U S A. 2011;108:18091–18096.
105. Montgomery CP, David MZ, Daum RS. Host factors that contribute to recurrent staphylococcal skin infection. Curr Opin Infect Dis. 2015;28:253–258.
106. Aly R, Maibach HI, Shinefield HR, et al. Bacterial interference among strains of Staphylococcus aureus in man. J Infect Dis. 1974;129:720–724.
107. Cohen JO, Smith PB, Shotts EB, et al. Bacterial interference: its effect on nursery-acquired infection with Staphylococcus aureus. VI. Detection of implanted Staphylococcus aureus strain. Use of serological and phage typing. Am J Dis Child. 1963;105:689–691.
108. ATCC. Staphylococcusaureus subsp. aureus Rosenbach (ATCC® 27217™). Available at: Accessed June 14, 2019.
109. Dubos R. Staphylococci and infection immunity. Am J Dis Child. 1963;105:643–645.
110. Light IJ, Sutherland JM, Schott JE. Control of a Staphylococcal outbreak in a nursery, use of bacterial interference. JAMA. 1965;193:699–704.
111. Houck PW, Nelson JD, Kay JL. Fatal septicemia due to Staphylococcus aureus 502A. Report of a case and review of the infectious complications of bacterial interference programs. Am J Dis Child. 1972;123:45–48.
112. Nouwen J, Fieren M, Snijders S, et al. Bacterial interference therapy with Staphylococcus aureus 502A for eradication of wild type S. aureus. 2004.In: 44th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Washington, DC: American Society for Microbiology.
113. Steele RW. Recurrent staphylococcal infection in families. Arch Dermatol. 1980;116:189–190.
114. Strauss WG, Maibach HI, Shinefield HR. Bacterial interference treatment of recurrent furunculosis. 2. Demonstration of the relationship of strain to pathogenicity. JAMA. 1969;208:861–863.
115. Smith CC, Bird EL, Carey-Smith KA. Bacterial substitution for staphylococcal infection. N Z Med J. 1968;67:407–409.
116. Fine RN, Onslow JM, Erwin ML, et al. Bacterial interference in the treatment of recurrent staphylococcal infections in a family. J Pediatr. 1967;70:548–553.
117. Orcutt R, Schaedler R. Heneghan JB. Control of staphylococci in the gut of mice. In: Germfree Research. 1973:New York, NY: New York Academy Press; 435–440.
118. Light IJ, Walton RL, Sutherland JM, et al. Use of bacterial interference to control a staphylococcal nursery outbreak. Deliberate colonization of all infants with the 502A strain of Staphylococcus aureus. Am J Dis Child. 1967;113:291–300.
119. Blair EB, Tull AH. Multiple infections among newborns resulting from colonization with Staphylococcus aureus 502A. Am J Clin Pathol. 1969;52:42–49.
120. Aly R, Shinefield HR, Litz C, et al. Role of teichoic acid in the binding of Staphylococcus aureus to nasal epithelial cells. J Infect Dis. 1980;141:463–465.
121. Otto M. MRSA virulence and spread. Cell Microbiol. 2012;14:1513–1521.
122. Tenover FC, Goering RV. Methicillin-resistant Staphylococcus aureus strain USA300: origin and epidemiology. J Antimicrob Chemother. 2009;64:441–446.
123. Miller LG, Eells SJ, Taylor AR, et al. Staphylococcus aureus colonization among household contacts of patients with skin infections: risk factors, strain discordance, and complex ecology. Clin Infect Dis. 2012;54:1523–1535.
124. Carey AJ, Della-Latta P, Huard R, et al. Changes in the molecular epidemiological characteristics of methicillin-resistant Staphylococcus aureus in a neonatal intensive care unit. Infect Control Hosp Epidemiol. 2010;31:613–619.
125. Graham PL III.. Transmission of USA-300 methicillin-resistant Staphylococcus aureus in a newborn nursery also affecting post-partum women [abstract]. 2008.In: 18th Annual Scientific Meeting. Orlando, FL: Society for Healthcare Epidemiology of America.
126. Cook HA, Furuya EY, Larson E, et al. Heterosexual transmission of community-associated methicillin-resistant Staphylococcus aureus. Clin Infect Dis. 2007;44:410–413.
127. Jones TF, Creech CB, Erwin P, et al. Family outbreaks of invasive community-associated methicillin-resistant Staphylococcus aureus infection. Clin Infect Dis. 2006;42:e76–e78.
128. Trinchieri G. Type I interferon: friend or foe? J Exp Med. 2010;207:2053–2063.
129. Parker D, Prince A. Staphylococcus aureus induces type I IFN signaling in dendritic cells via TLR9. J Immunol. 2012;189:4040–4046.

bacterial competition; host immune response; invasiveness; strain 502A

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